Antithyroid compounds



Patented Mar. 2, 1954 Q UNITED STATES" PATENT OFFICE- REISSUED son,

ANTITHYROID COMPOUNDS Claude Rimington, New Barnet, Alexander Law- Southgate, London,

- Searle, Wandsworth Common, London, and Harold Victor Morley, Denmark Hill, London,

Charles Edmund England, assignors to National Research Development Corporation, London, England, a

British corporation No Drawing. Application March 24, 1952,

. Serial No. 278,308

I Claims priority, applgcaigigii Great Britain April 6 Claims. (Cl. 260309) 1 This invention comprises new anti-thyroid compounds.

It is known that 1-methyl-2-mercaptogly oxaline is a very potent anti-thyroid agent. Its activity is much greater than thiouracil, the drug in most common use. 1

The new compounds of the present invention have the formula:

I I ")NB is a CH=CH CH=CH I 010GB I I /NR N /NR O a an 5.00.111 The R-substituted 2-mercaptoglyoxalines phenylisothiocyanate) followed, if necessary, by'

treatment of the so formed substituted thiourea with acid to efl'ect ring closure.

a The following examples are given in illustra- Example 1.Preparation of i-methyl-Z-carbeihorythioglyoxaline 0.1 mol. of 1-methyl-Z-mercaptoglyoxaline is dissolved in the minimum quantity of pyridine v2 at 0 C. 0.1 mol. of ethyl-chloroformate is added dropwise with stirring. More yridine is added, if necessary, to keep the mixture semi-fluid. The sludge is thenplaced in an ice-box for 30 minutes. The crystals are filtered 011 and washed firstly with a little ethanol and secondly with ethanol and water. The product is crystallised from the solvent to give colourless needles having a melt-- ing point of 122-3 C. Found: C, 45.7; H, 5.4. C'IH10O2N2S requires C, 45.2, H, 5.4%.

Example 2.Preparation of i-methyl-Z-carbomethoxythioglyoraline The procedure of Example 1 is followed but substituting methyl chloroiormate for the ethyl ester. The product, recrystallised from ethanol, has a melting point of 135 C. Found: C, 41.7: H, 4.4. CsI-laOzNzS requires C, 41.8; H, 4.6%.

Example 3.--Preparation of 1-methyl2-carbobenzoxythioglyozaline (a) 0.1 mol of 1-methyl-2-mercaptoglyoxaline is dissolved in the minimum amount of pyridine at 0 C. 0.1 mol of carbobenzoxy chloride is added dropwise with stirring. The solution is then stirred for -1 hour at room-temperature and laced in a vacuum desiccator over concentrated H2SO4/KOH.

The sticky oil is rubbed under petroleum-ether and the solvent poured off. This is repeated twice. The thick oil is then rubbed under water which causes it to crystallise slowly. The white crystalline material is filtered off. On recrystallisation from benzene/petroleum-ether (60- C.) the product is obtained in white needles having a melting point of 91-92 C. (b) 0.1 mol of 1-methyl-2-mercaptoglyoxaline is dissolved in 50 m1. of 4 N-caustic soda at 0 C. 0.1 mol. of carbobenzoxy chloride is added slowly. After the addition, the mixture is stirred at 0 C. for 15-30 minutes. The reaction mixture is then placed in an ice-box for hour, the white solid filtered oil and washed firstly with water and secondly with petroleum-ether. The solid is crystallised from benzene/petroleum-ether to give white needles having a melting point of 91-92 0.

Found: C, 58.3; H, 4.9. C12H1202N2S requires C. 58.1; H, 4.9%.

Example 4.--Preparation of 1-methyl-2-hlppurylthioglyoraline 3 ice water with stirring. The small crystals appeering are then removed by filtration and re.- crystallised several times from ethyl acetate in which they are rather sparingly soluble. This gives a colourless microcrystalllne product, M. P. 175 C. Found C, 56.4; H, 4.9; N, 15.3%. CuHisOzNaS requires C, 56.9; H, 4.7; N, 15.3%.

Example 5.-Preparation of di-(I-methyl-Z-ylyomalinul) dithiolcarbonate dihydrochloride 0.01 mol. of 1-methy1-2-mercaptoglyoxaline is dissolved in 30 ml. dry benzene and 0.01 mol. phosgene dissolved in toluene is added slowly with cooling. The reddish coloured precipitate is filtered oil and recrystallised from alcohol containing a small amount of .water. Colourless needles M. P. 167 0. Found: C. 32.3; H, 4.196. CaI-ImOmSzChm-O requires C, 31.4; H, 4.07%.

We claim:

1. As a new anti-thyroid compound, a. substance selected from the group consisting oi 1-methyl-2-carhethoxythioglyoxaline, l-methyl- 2 carbomethoxythioglyoxaline, l-methyl-Z-carbobenzoxythioglyoxaline, 1 methyl-2-hippurylstance 1-methyl-2-hippurylthioglyoxalin.

6. As a. new anti-thyroid compound, the substance di (l-methyl-z-glyoxalinyl) dithiolcarbonate dihydrochloride.

CLAUDE RIMINGTON. ALEXANDER LAWSON. CHARLES EDMUND SEARLE. HAROLD VICTOR MORLEY.

References Cited in the tile of this patent UNITE!) STATES PATENTS Number Name Date 2,519,310 Dessert Aug. 15, 1950 2,585,388 Jones Feb. 12, 1952 

1. AS A NEW ANTI-THYROID COMPOUND, A SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF 1-METHYL-2-CARBETHOXYTHIOGLYOXALINE, 1-METHYL2 - CARBOMETHOXYTHIOGLYOXALINE, 1-METHYL-2-CARBOBENZOXYTHIOGLYOXALINE, 1-METHYL-2-HIPPURYLTHIOGLYOXALINE AND DI-(1-METHYL-2-GLYOXALINYL) DITHIOLCARBONATE DIHYDROCHLORIDE. 